The retina is a thin layer of neural tissue lining the inner surface of the back of the eye. The retina consists of various kinds of neurons, the most familiar of which are the photoreceptors responsible for vision: rods, which are more sensitive to light, and cones, which are more sensitive to color. The cones are highly concentrated in the macula, the small, central portion of the retina. It is this portion of the eye that is responsible for central, high acuity vision.
Diseases of the retina, and the macula in particular, are the leading cause of vision impairment and blindness in those over 50 years of age in developed countries. These diseases include age-related macular degeneration, myopic macular degeneration, diabetic macular edema, diabetic retinopathy, branch retinal vein occlusion, and central retinal vein occlusion. Macular degeneration can occur in children, as well.
Some of these diseases can be treated with agents that inhibit a protein called vascular endothelial growth factor A (VEGF-A). VEGF-A stimulates the growth of blood vessels. In the exudative (or vascular) form of age-related macular degeneration, abnormally high levels of VEGF stimulate the growth of new blood vessels into the macula causing irreversible damage to photoreceptors; in addition, these newly formed blood vessels leak blood and proteins into the retina, causing a scar to form in the area that was previously occupied by photoreceptors. Inhibiting VEGF-A blocks the formation of these new vessels, and blocks the leakage of blood and proteins, thus preserving vision.
There are a few drugs that are used to inhibit VEGF-A in the eye. These include ranibizumab, bevacizumab, aflibercept, and, to a lesser extent, pegaptanib. They are effective to various degrees, but all suffer from two significant shortcomings: they are not effective in all patients, and they must be dosed frequently (at least every four to eight weeks) by a method of administration which many patients find disagreeable.
Ranibizumab is a antibody fragment derived from the same parent mouse antibody as bevacizumab. It is sold under the brand name LUCENTIS® in the United States. Ranibizumab is indicated for the treatment of neovascular (exudative) age-related macular degeneration, macular edema following retinal vein occlusion, and diabetic macular edema.
Ranibizumab is administered at a dose of 0.3 mg or 0.5 mg, depending on the condition treated, every 28 days. The drug is injected by means of syringe directly into the vitreous humor of the eye, the clear gelatinous material that comprises most of the volume of the eye. An example is shown in FIG. 1. An intravitreal injection can be injected through the pars plana, 3 mm to 4 mm posterior to the limbus. For age-related macular degeneration, 0.5 mg ranibizumab is administered to the affected eye by intravitreal injection approximately every 28 days. The prescribing literature that accompanies the product states that “treatment may be reduced to one injection every 3 months after the first four injections if monthly injections are not feasible,” but that such doses are “less effective,” and that “dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months” compared to continued monthly dosing.
Bevacizumab is a humanized monoclonal antibody inhibitor of VEGF-A. It is sold under the brand name AVASTIN® in the United States. Bevacizumab is indicated as a single-use therapy for glioblastoma and as an adjunctive therapy for metastatic colorectal cancer, non-squamous non-small cell lung cancer, and metastatic renal cell carcinoma. It is also used, off-label, for the treatment of those conditions for which ranibizumab is indicated. The dosing schedule is the same as for ranibizumab.
Aflibercept is a recombinant fusion protein comprising extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. It is sold under the brand name EYLEA® in the United States. Aflibercept is indicated for the treatment of neovascular (exudative) age-related macular degeneration, administered in a 2 mg dose by intravitreal injection every 4 weeks for the first 12 weeks, followed by 2 mg via intravitreal injection once every 8 weeks. The drug may also be dosed as frequently as 2 mg every 4 weeks.
Pegaptanib is a single strand of nucleic acid, more specifically, an oligonucleotide of twenty-eight nucleotides, that binds to VEGF-A165. It is sold under the brand name MACUGEN® in the United States. Pegaptanib is approved for the treatment of treatment of neovascular (exudative) age-related macular degeneration, administered in a 0.3 mg dose every 6 weeks by intravitreous injection. The drug is not as effective as ranibizumab, bevacizumab, or aflibercept and so is not as frequently used.
Despite the effectiveness of ranibizumab, bevacizumab, aflibercept, and pegaptanib, there are still patients who do not respond to those drugs. Moreover, those drugs require frequent administration every four to eight weeks. That may not seem so bad—and indeed it would not be so, were those drugs swallowed as a pill, or applied topically as an eye drop. Instead, those drugs are administered by a needle that pierces the front of the eye (including, but not limited to the conjunctiva and sclera) and extends into the vitreous of the eye where the drug is delivered. The procedure is safe, when performed by trained personnel, but readers who doubt that anyone should object to undergoing such a procedure every four weeks are invited to take a needle, hold it within proximity to the eye, and contemplate the path required to reach the vitreous. There is therefore a need in the art for therapies capable of treating patients who desire a relief from diseases of the retina whom ranibizumab, bevacizumab, aflibercept, or pegaptanib do not aid, for patients who desire less frequent treatment, and for patients desire both.